It has become increasingly clear that the earliest phases of Mycobacterial infection, involving the innate immune response, set the stage for future progression or resolution of disease. The embryonic zebrafish provides a unique system in which to study innate immunity, as the cellular components of the immune system have yet to develop. Additionally, the optical transparency of the embryo allows for direct in vivo observation of pathogenesis. My project will take two approaches to further refine our understanding of innate pathogenesis of mycobacterial infection. A candidate gene approach will be used to investigate the role of Interferon Gamma (IFNg) in our system, an immune cytokine known to be important to the adaptive immune response to tuberculosis. The second aim will be directed towards the identification of novel host genes important to the innate response to tuberculosis. This project will utilize a forward genetic screen previously conducted by our group, identification of mutant fish differentially susceptible to infection, and mapping of the causative lesion to a specific locus using next-generation DNA sequencing technology. PUBLIC HEALTH RELEVANCE: Much more has to be learned before tuberculosis can be adequately controlled. The early interactions of tuberculosis infection with the innate immune system strongly influence later outcomes. This study will better our understanding of an immune signal, Interferon gamma, and seeks to discover new genes that affect the host's ability to resist infection.